This application is the National Phase filing of International Patent Application No. PCT/JP01/01483, filed Feb. 28, 2001.
The present invention relates to novel thienopyridine derivatives or salts thereof, which have anti-inflammatory activity, bone resorption suppressive activity, immune cytokine production suppressive activity, etc., and are useful as medicaments such as anti-arthritis drugs, etc., and to their production and use.
Arthritis is an inflammatory disease of joints, which includes, as major diseases, rheumatoid arthritis and related diseases with inflammation observed in joints.
Among them, rheumatoid arthritis, also called chronic rheumatoid arthritis, is a chronic polyarthritis that is characterized by inflammatory changes in the synovia in the internal capsules of joints as the major lesion. Arthritis such as rheumatoid arthritis is a progressive disease, which brings about joint dysfunctions such as joint deformity, arthrokleisis, and the like, and often leads to serious disability if it is exacerbated without being treated effectively.
Heretofore, drugs available for treating these arthritides have been steroids such as corticosteroids (e.g., cortisone, etc.), non-steroidal anti-inflammatory drugs (e.g., aspirin, piroxicam, indomethacin, etc.), gold compounds (e.g., aurothiomalate, etc.), antirheumatic drugs (e.g., chloroquine preparation, D-penicillamine, etc.), gout suppressants (e.g., colchicines, etc.), immunosuppressants (e.g., cyclophosphamide, azathioprine, methotrexate, levamisole, etc.) and the like. However, some of these drugs have been problematic such as serious adverse reactions, adverse reactions precluding a long-term administration, insufficient efficacy, lack of effect on established arthritis or the like.
Thienopyridine derivatives or thienodipyridine derivatives have been reported as anti-inflammatory drugs, especially as remedies for arthritis, in JP 8-225577 A (PCT International Application Publication No. WO96/14319); JP 10-36374 A (PCT International Application Publication No. WO97/40050), and PCT International Application Publication No. WO97/65916 and the like.
Medicaments with superior prophylactic and therapeutic efficacy against arthritis and the like have been still desired for the clinical treatment of arthritis and the like.
Under these circumstances, the present inventors have studied intensively and, as a result, the present inventors have found that novel thienopyridine derivatives, which are represented by the following formula (I) and are characteristic in ring B and group G in the 3-position, are useful as suppressants of joint destruction by possessing potent anti-inflammatory activity, in particular antiarthritic activity, are useful as bone resorption suppressants by possessing the excellent bone resorption suppressing activity with direct effect on the bone, and further are useful as immunosuppressants. The present inventors have further studied based on these findings. Thus the present invention has been completed.
That is, the present invention relates to:
(1) A compound represented by the formula (I): 
wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group; alk represents an optionally substituted lower alkylene group; X represents oxygen atom, an optionally oxidized sulfur atom, or xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5); R represents an optionally substituted amino group or an optionally substituted heterocyclic group; ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y represents oxygen atom, an optionally oxidized sulfur atom, 
(wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring; and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group); and ring A represents an optionally substituted benzene ring, or a salt thereof;
(2) The compound according to the above (1), wherein alk is methylene;
(3) The compound according to the above (1), wherein G is a halogen atom;
(4) The compound according to the above (1), wherein G is chlorine atom;
(5) The compound according to the above (1), wherein X is xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5);
(6) The compound according to the above (1), wherein X is a bond;
(7) The compound according to the above (1), wherein the optionally substituted amino group represented by R is xe2x80x94N(R1) (R2) (wherein R1 and R2, which may be the same or different, respectively, represent hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted acyl, sulfonyl, sulfinyl, or heterocyclic group, or R1 and R2 may be combined each other to form an optionally substituted nitrogen-containing 5- to 7-membered heterocyclic group);
(8) The compound according to the above (7), wherein R1 and R2 are combined each other to form a nitrogen-containing optionally substituted 5- to 7-membered heterocyclic group;
(9) The compound according to the above (7), wherein R1 and R2 are acyl groups;
(10) The compound according to the above (1), wherein R is an optionally substituted nitrogen-containing heterocyclic group;
(11) The compound according to the above (1), wherein the substituent on the optionally substituted heterocyclic group represented by R is oxo group;
(12) The compound according to the above (1), wherein R is 
wherein ring C represents a 5- to 7-membered heterocyclic group optionally containing one or more hetero atoms selected from nitrogen, sulfur and oxygen atoms, in addition to the nitrogen atom;
(13) The compound according to the above (1), wherein ring B is an optionally substituted 6-membered ring containing Y;
(14) The compound according to the above (1), wherein the substituents on ring B are one to four substituents selected from a C1-6 alkyl group and a halogen atom;
(15) The compound according to the above (1), wherein ring B is a ring represented by the formula: 
wherein Yxe2x80x2 and Yxe2x80x3 represent carbon atom, sulfur atom or oxygen atom, respectively; n represents an integer of 0 to 4; and Y is as defined in the above 1, which may be substituted with one to four substituents selected from a C1-6 alkyl group and a halogen atom;
(16) The compound according to the above (1), wherein Y is an optionally oxidized sulfur atom or 
(17) The compound according to the above (1), wherein ring A is benzene ring which may be substituted with one to four substituents selected from a halogen atom, nitro group, an optionally substituted alkyl group, an optionally substituted hydroxyl, an optionally substituted thiol group, an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group, and an optionally substituted aromatic ring group;
(18) The compound according to the above (1), wherein the substituent on ring A is a C1-6 alkoxy group or hydroxyl group;
(19) The compound according to the above (1), wherein the compound represented by formula (I) is:
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methly}-2,5-pyrrolidinedione ethylene ketal;
3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione or an optically active substance thereof or a salt thereof;
3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-oxazolidine-2,4-dione or an optically active substance thereof or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or an optically active substance thereof or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro [1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
3-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof; or
2-aminomethyl-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3:4,5]thieno[2,3-b]pyridine or an optically active substance thereof or a salt thereof;
(20) The compound according to the above (1), wherein the compound represented by formula (I) is:
3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione or an optically active substance thereof or a salt thereof;
3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-oxazolidine-2,4-dione or an optically active substance thereof or a salt thereof; or
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or an optically active substance thereof or a salt thereof;
(21) The compound according to the above (1), wherein the compound represented by formula (I) is:
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
3-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione or a salt thereof; or
1-{[3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
(22) The compound according to the above (1), wherein the compound represented by formula (I) is:
1-{[3-chloro-4-(4-hydroxyphenyl)-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl }-2,5-pyrrolidinedione or a salt thereof;
4-{3-chloro-2-[2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-4-yl}phenyl} diisobutyl phosphate or a salt thereof; or
butyl 4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4 ,3xe2x80x2:4,5]thieno[2,3-b]pyridin-4-yl}phenyl carbonate or a salt thereof;
(23) A prodrug of the compound according to the above (1);
(24) A process for producing a compound represented by the general formula (I): 
wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group; alk represents an optionally substituted lower alkylene group; X represents oxygen atom, an optionally oxidized sulfur atom, or xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5); R represents an optionally substituted amino group or an optionally substituted heterocyclic group; ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y represents oxygen atom, an optionally oxidized sulfur atom, 
(wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring; and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group); and ring A represents an optionally substituted benzene ring, or a salt thereof which comprises reacting a compound represented by the formula (II-1): 
wherein Q represents a leaving group; and the other symbols are as defined above, or a salt thereof, with a compound represented by the formula (III):
Rxe2x80x94X1Hxe2x80x83xe2x80x83(III)
wherein R is as defined above; and X1 represents oxygen atom, or an optionally oxidized sulfur atom, or a salt thereof to obtain a compound represented by the formula (I-1): 
wherein each symbol is as defined above, or a salt thereof; or
reacting a compound represented by the formula (II-2): 
wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula (IV): 
wherein R1 and R2, which may be the same or different, respectively, represent an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted sulfonyl group, or an optionally substituted heterocyclic group, or R1 and R2 may be combined each other to form an optionally substituted nitrogen-containing 5- to 7-membered ring, or a salt thereof to obtain a compound represented by the formula (I-2): 
wherein each symbol is as defined above, or a salt thereof; or
subjecting a compound represented by the formula (I-3): 
wherein ring B1 represents an optionally substituted Y1-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y1 represents sulfur atom or 
and the other symbols are as defined above, or a salt thereof to oxidation to obtain a compound represented by the formula (I-4): 
wherein ring B2 represents an optionally substituted Y2-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y2 represents an oxidized sulfur atom or 
and the other symbols are as defined above, or a salt thereof; or
reacting a compound represented by the formula (II-3): 
wherein Gxe2x80x2 represents a halogen atom; and the other symbols are as defined above, or a salt thereof, with
(C6H5)3P
in a solvent to obtain a compound represented by formula (VI): 
wherein each symbol is as defined above, then reacting the compound represented by the formula (VI) with a compound represented by the formula (VII):
Z1xe2x80x94(CH2)qxe2x80x2CHOxe2x80x83xe2x80x83(VII)
wherein Z1 represents an optionally substituted heterocyclic group; and qxe2x80x2 represents an integer of 0 to 4, or a salt thereof to obtain a compound represented by formula (VIII): 
wherein each symbol is as defined above, or a salt thereof, and further subjecting the compound represented by formula (VIII) or a salt thereof to reduction to obtain a compound represented by the formula (I-5): 
wherein each symbol is as defined above, or a salt thereof; or
reacting a compound represented by the formula (II-1): 
wherein each symbol is as defined above, or a salt thereof, with a compound represented by formula (XII):
Rxe2x80x94Hxe2x80x83xe2x80x83(XII)
wherein R is as defined above, or a salt thereof to obtain a compound represented by the formula (I-9): 
wherein each symbols is as defined above, or a salt thereof;
(25) A pharmaceutical composition comprising a compound represented by the general formula (I): 
wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group; alk represents an optionally substituted lower alkylene group; X represents oxygen atom, an optionally oxidized sulfur atom, or xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5); R represents an optionally substituted amino group or an optionally substituted heterocyclic group; ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y represents oxygen atom, an optionally oxidized sulfur atom, 
(wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring; and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group); and ring A represents an optionally substituted benzene ring, a prodrug thereof, or a pharmaceutically acceptable salt thereof;
(26) The pharmaceutical composition according to the above (25) for prevention or treatment of inflammatory diseases;
(27) The pharmaceutical composition according to the above (25) for prevention or treatment of arthritis;
(28) The pharmaceutical composition according to the above (25) for prevention or treatment of rheumatism;
(29) The pharmaceutical composition according to the above (25) for prevention or treatment of chronic rheumatoid arthritis;
(30) The pharmaceutical composition according to the above (25), which is a bone resorption suppressant;
(31) The pharmaceutical composition according to the above (25) for prevention or treatment of osteoporosis;
(32) The pharmaceutical composition according to the above (25), which is a suppressant of cytokine production;
(33) The pharmaceutical composition according to the above (25) for prevention or treatment of autoimmune diseases;
(34) The pharmaceutical composition according to the above (25) for prevention or treatment of rejection reaction after organ transplantation;
(35) The pharmaceutical composition according to the above (25), which is a T-cell differentiation-controlling medicament.
(36) A method for preventing or treating inflammatory diseases which comprises administering an effective amount of a compound represented by the formula (I): 
wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group; alk represents an optionally substituted lower alkylene group; X represents oxygen atom, an optionally oxidized sulfur atom, or xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5); R represents an optionally substituted amino group or an optionally substituted heterocyclic group; ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y represents oxygen atom, an optionally oxidized sulfur atom, 
(wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring; and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group); and ring A represents an optionally substituted benzene ring, a prodrug thereof, or a pharmaceutically acceptable salt thereof, to a mammal in need of the prevention or treatment; and
(37) Use of a compound represented by the formula 
wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group; alk represents an optionally substituted lower alkylene group; X represents oxygen atom, an optionally oxidized sulfur atom, or xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5); R represents an optionally substituted amino group or an optionally substituted heterocyclic group; ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y represents oxygen atom, an optionally oxidized sulfur atom, 
(wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring; and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group); and ring A represents an optionally substituted benzene ring, a prodrug thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for preventing or treating inflammatory diseases.
The explanation of all definitions included in the above-mentioned general formulas and in the scope of the present invention as well as preferred examples thereof will be described below.
In the above formula (I), G represents a halogen atom (e.g., chlorine, bromine, iodine or fluorine); hydroxyl group, an optionally substituted amino group [e.g., amino group, a Nxe2x80x94(C1-6 alkyl)amino group such as methylamino, ethylamino, propylamino, butylamino, etc.; a N,N-di(C1-6 alkyl)amino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.]; an optionally substituted lower alkyl group [e.g., a C1-6 alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.) which may be substituted with one to three halogen atoms]; or an optionally substituted lower alkoxy group [e.g., a C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, etc.) which may be substituted with 1 to 3 halogen atoms]. A preferred example of G is a halogen atom with chlorine being more preferred.
In the above formula, Gxe2x80x2 represents a halogen atom (e.g., chlorine, bromine, iodine or fluorine). A preferred example of Gxe2x80x2 is chlorine.
Examples of the lower alkylene group of the optionally substituted lower alkylene group represented by alk include a C1-6 alkylene group such as methylene, ethylene, propylene, and the like.
Examples of the substituents of the lower alkylene group represented by alk include 1 to 4 substituents selected from a halogen atom (e.g., chlorine, bromine, iodine or fluorine), hydroxyl group, an optionally substituted amino group [e.g., amino group, a Nxe2x80x94(C1-6 alkyl)amino group such as methylamino, ethylamino, propylamino, butylamino, etc.; a N,N-di(C1-6 alkyl)amino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.], a optionally substituted lower alkyl group [e.g., a C1-6 alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.) which may be substituted with 1 to 3 halogen atom, etc.], and an optionally substituted alkoxy group [e.g., a C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, etc.) which may be substituted 1 to 3 halogen atom, etc.].
In the above formula (I), X represents oxygen atom, an optionally oxidized sulfur atom, or xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5, preferably an integer of 0 to 3, and more preferably 0). As the optionally oxidized sulfur atom represented by X, there is thio group, sulfinyl group, and sulfonyl group, with thio group being preferred.
Preferably, X is xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5, preferably an integer of 0 to 3, and more preferably 0).
In the above formula (I), examples of the optionally substituted amino group represented by R include a group represented by the formula: xe2x80x94N(R1) (R2) (wherein R1 and R2, which may be the same or different, respectively, represent hydrogen atom or a hydrocarbon group, an acyl group, sulfonyl group, sulfinyl group or a heterocyclic group (preferably an acyl group), which respectively may be substituted, or R1 and R2are combined each other to form an optionally substituted nitrogen-containing heterocyclic ring), and the like.
Examples of the hydrocarbon group in the optionally substituted hydrocarbon group represented by R1 or R2 include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, an aromatic aliphatic hydrocarbon group, an aromatic hydrocarbon group, and the like.
Examples of said aliphatic hydrocarbon group include a C1-8 saturated aliphatic hydrocarbon group (e.g., C1-8 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.), a C2-8 unsaturated aliphatic hydrocarbon group (e.g., C2-8 alkenyl, C2-8 alkynyl, C4-8 alkadienyl, and C4-8 alkadiynyl, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadlynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, etc.), and the like.
Examples of said alicyclic hydrocarbon group include C3-7 saturated alicyclic hydrocarbon group (e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) and C5-7 unsaturated alicyclic hydrocarbon group (e.g., C5-7 cycloalkenyl and C5-7 cycloalkadienyl such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, etc.) and the like.
Examples of said alicyclic-aliphatic hydrocarbon group include, among the residues formed by combination of the above-mentioned alicyclic hydrocarbon groups and the above-mentioned aliphatic hydrocarbon groups, that having 4 to 9 carbon atoms such as cycloalkylalkyl, cycloalkylalkeny, and the like, each of which having 4 to 9 carbon atoms (e.g., cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cyclobutylethyl, etc.).
Examples of said aromatic alicyclic hydrocarbon group include C7-9 phenylalkyl (e.g., benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, etc.) and C11-13 naphthylalkyl (e.g., xcex1-naphthylmethyl, xcex1naphthylethyl, xcex2-naphthylmethyl, xcex2-naphthylethyl, etc.) and the like.
Examples of said aromatic hydrocarbon group include phenyl, naphthyl (xcex1-naphthyl and xcex2-naphthyl), and the like.
As for the hydrocarbon group in the optionally substituted hydrocarbon group represented by R1 or R2, C1-6, straight chain or branched chain alkyl, particularly C1-4, straight chain alkyl or C3-4, branched chain alkyl is preferred. Specifically, groups such as methyl, ethyl, propyl, isopropyl, butyl, and the like are preferred.
Examples of the acyl group in the optionally substituted acyl group represented by R1 or R2 include (i) formyl, or (ii) groups where the carbonyl group is combined to a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, C3-7 cycloalkyl, C5-7 cycloalkenyl, or an aromatic group (e.g., phenyl group, pyridyl group, etc.), (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).
Examples of the sulfonyl group in the optionally substituted sulfonyl group represented by R1 or R2 include groups where the sulfonyl group is combined to a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, C3-7 cycloalkyl, C5-7 cycloalkenyl, or an aromatic group (e.g., phenyl group, pyridyl group, etc.), (e.g., methanesulfonyl, ethanesulfonyl, benzenesulfonyl, etc.).
Examples of the sulfinyl group in the optionally substituted sulfinyl group represented by R1 or R2 include groups where the sulfinyl group is combined to a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, C3-7 cycloalkyl, C5-7 cycloalkenyl, or an aromatic group (e.g., phenyl group, pyridyl group, etc.), (e.g., methanesulfinyl, ethanesulfinyl, benzenesulfinyl, etc.).
Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R1 or R2 include (i) 5- to 7-membered heterocyclic groups containing one sulfur atom, one nitrogen atom, or one oxygen atom, (ii) 5- to 6-membered heterocyclic groups containing 2-4 nitrogen atoms, (iii) 5- to 6-membered heterocyclic groups containing 1-2 nitrogen atoms and one sulfur or oxygen atom, or the like, and (iv) these heterocyclic groups may be condensed with a 5- to 6-membered ring containing 2 or less nitrogen atoms, benzene ring, or a 5-membered ring containing one sulfur atom. In addition, each of the heterocyclic groups exemplified in (i) to (iv) may be a saturated or unsaturated heterocyclic group and the unsaturated heterocyclic group may be either aromatic or non-aromatic.
Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R1 and R2 include an aromatic-monocyclic heterocyclic group, an aromatic condensed heterocyclic group, and a non-aromatic, heterocyclic group.
Specific examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R1 and R2 include (i) an aromatic-monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.), (ii) an aromatic condensed heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl, benzooxazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.), and (iii) a non-aromatic, heterocyclic group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.).
In the case where R1 and R2 are combined each other to form a ring, particularly a nitrogen-containing 5- to 7-membered ring, examples of such xe2x80x94N(R1) (R2) include 1-pyrrolyl, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperidyl (piperidino), 1-piperazinyl, 4-morpholinyl (morpholino), 4-thiomorpholinyl, homopiperazin-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,3-thiadiazol-3-yl, 1,3-oxadiazol-3-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-2-yl, tetrazol-1-yl, oxazol-3-yl, thiazol-3-yl, and a partly or whole saturated nitrogen-containing heterocyclic group thereof. These heterocyclic groups may have the 1 to 3 same substituents as those of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group as described hereinafter, and may be condensed with the above-mentioned aromatic, monocyclic heterocyclic group or an aromatic ring such as benzene ring or the like. Specific examples in the case where the heterocyclic group condensed with the aromatic ring include benzimidazol-1-yl, indol-1-yl, 1H-indazol-1-yl, and the like; preferably, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, imidazol-1-yl, morpholino (4-morpholinyl), piperidino (1-piperidyl), oxazolidin-3-yl, thiazolidin-3-yl, hydantoin-1-yl, pyrrolidino (1-pyrrolidin-1-yl) and the like, each of which may be substituted and may be condensed with benzene ring; more preferably, a nitrogen-containing 5- to 7-membered ring that may have 1 to 2 oxo groups (e.g., 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl, 2,5-dioxohydantoin-1-yl, 2,5-dioxopyrrolidin-1-yl, etc.), with 2,5-dioxopyrrolidin-1-yl being particularly preferred.
The hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 may have 1 to 3 substituents at any possible positions on the chain or the ring thereof.
Examples of such a substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include an aliphatic-chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic, heterocyclic group, a non-aromatic, heterocyclic group, a halogen atom, an optionally substituted amino group, amidino group, an optionally substituted acyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified or amidated carboxyl group, an aralkyl group (e.g., a C6-14 aryl-C1-6 alkyl group, etc.), a carbamoyl group, an optionally substituted thocarbamoyl group, an N-mono-substituted carbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), an N,N-disubstituted carbamoyl group (N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, piperidinocarbamoul, morpholinocarbamoyl, etc.), a sulfamoyl group, an N-mono-substituted sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, p-toluenesulfamoyl, etc.), an N,N-disubstituted sulfamoyl group (e.g., N,N-dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfamoyl, morpholinosulfamoyl, etc.), mercapto group, sulfo group, cyano group, azido group, nitro group, nitroso group, oxo group, and the like.
Examples of the aliphatic-chain hydrocarbon group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include a straight or branched chain aliphatic hydrocarbon group such as an alkyl group (preferably, a C1-10 alkyl group), an alkenyl group (preferably, a C2-10 alkenyl group), an alkynyl group (preferably, a C2-10 alkynyl group), and the like. Preferred examples of said alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl, and the like. Preferred examples of said alkenyl group include vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like. Preferred examples of said alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.
Examples of the alicyclic hydrocarbon group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include a saturated or unsaturated C3-8 alicyclic hydrocarbon group such as a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C4-8 cycloalkadienyl group and the like. Preferred examples of said C3-8 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and the like. Preferred examples of said C3-8 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, and the like. Preferred examples of said C4-8 cycloalkadienyl group include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, and the like.
The aryl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2, and the aryl group in the aralkyl group mean a monocyclic, or condensed polycyclic aromatic hydrocarbon group. Preferred examples thereof include phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, and the like, with C6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, and the like being more preferred.
Examples of an optionally substituted thiocarbamoyl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include methylthiocarbamoyl, ethylthiocarbamoyl, phenylthiocarbamoyl and the like.
Preferred examples of the aromatic heterocyclic group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include an aromatic monocyclic heterocyclic group (e.g., a 5- to 6-memberd aromatic, monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms, such as furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pirazinyl, triazinyl, etc.) as well as an aromatic condensed heterocyclic group (e.g., a 8- to 12-memberd aromatic, monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl, benzooxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b]pyridazinyl, pyrazo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.), and the like.
Preferred examples of the non-aromatic heterocyclic group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include a 5- to 8-membered non-aromatic, monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms, such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like.
Examples of the halogen atom as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include fluorine, chlorine, bromine, and iodine, with fluorine and chlorine being particularly preferred.
Examples of the optionally substituted amino group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include amino group, an N-mono-substituted amino group, and N,N-disubstituted amino group. Examples of said substituted amino groups include an amino group having one or two C1-10 alkyl groups, C3-7 cycloalkyl groups, C2-10 alkenyl groups, C2-10 alkynyl groups C3-7 cycloalkenyl groups, C6-14 aryl groups that may have a C1-4 alkyl group, a heterocyclic group (e.g., the same heterocyclic group as that as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, and the heterocyclic group represented by R1 or R2), or C1-10 acyl groups (e.g. C3-7 alkanoyl, etc.) as the substituents thereof (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.). In addition, the two groups in said substituted amino group may be combined to form a nitrogen-containing, 5- to 7-membered ring (e.g., the same ring as that formed by combining R1 and R2 each other, preferably, piperidine, morpholino, thiomorpholino, etc.).
Further, the carbamoyl group and the sulfamoyl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 may have the same one or two substituents as those of the above-mentioned substituted amino group.
Examples of the optionally substituted acyl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include (i) formyl or (ii) a group where the carbonyl group is combined with a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-7 cycloalkyl group, a C5-7 cycloalkenyl group, or an aromatic group (e.g., phenyl group, pyridyl group, etc.) (e.g., acetyl, propionyl, butyryl, isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, etc.) and the like.
Examples of the optionally substituted hydroxyl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include hydroxyl group and a hydroxyl group having an appropriate substituent, particularly, that to be used as a protective group (e.g., alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyloxy, aryloxy, etc.).
As the preferred alkoxy, there is C1-10 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, etc.), C3-7 cycloalkyloxy (e.g., cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.).
As the preferred alkenyloxy, there is C2-10 alkenyloxy (e.g., allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, etc.) or C3-7 cycloalkyloxy (e.g., 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.).
As the preferred alkynyloxy, there is C2-10 alkynyloxy (e.g., ethynyloxy, 2-propinyloxy, etc.).
As the preferred aralkyloxy, there is, for example, phenyl-C1-4 alkyloxy (e.g., benzyloxy, phenethyloxy, etc.).
As the preferred acyloxy, there is C2-4 alkanoyloxy (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.), C3-4 alkenoyloxy, or C3-4 alkynoyloxy.
As the preferred aryloxy, there is phenoxy, a phenoxy optionally substituted with a halogen atom such as 4-chlorophenoxy, or the like.
Examples of the optionally substituted thiol group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include thiol group and a thiol group having an appropriate substituent, particularly, that to be used as a protective group (e.g., alklythio, alkenylthio, alkynylthio, aralkylthio, acylthio, arylthio, etc.), and examples of said substituent include the same substituent as that of the optionally substituted hydroxyl group.
Examples of the optionally esterified carboxyl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include, in addition to carboxyl group, an alkyloxycarbonyl group, an alkenyloxycarbonyl, an alkynyloxycarbonyl, an aralkyloxycarbonyl group, an acyoxycarbonyl group, an aryloxycarbonyl group, and the like.
Examples of the alkyl group in said alkyloxycarbonyl group include a C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.).
Examples of the alkenyl group in said alkenyloxycarbonyl group include a C2-6 alkenyl group (e.g., vinyl, allyl, isopropenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-methylallyl, etc.).
Examples of the alkynyl group in said alkynyloxycarbonyl group include a C2-6 alkynyl group (e.g., ethynyl, 2-propynyl, etc.).
The aralkyl group in said aralkyloxycarbonyl group means an aryl-alkyl group (e.g., C6-10 aryl-C1-6 alkyl, etc.). The aryl group in said aryl-alkyl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group, and preferred examples include phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, and the like. They may have a substituent such as a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C4-8 cycloalkadienyl group, an aryl group (e.g., C6-14 aryl, etc.), an aromatic heterocyclic group (e.g., the same aromatic heterocyclic group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2, etc.), a non-aromatic heterocyclic group (e.g., the same non-aromatic heterocyclic group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2, etc.), an aralkyl group (e.g., a C6-14 aryl-C1-6 alkyl group, etc.), amino group, an N-mono-substituted amino group (e.g., the same N-mono-substituted amino group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2, preferably a N-mono-C1-4 alkylamino group, etc.), a N,N-disubstituted amino group (e.g., the same N,N-disubstituted amino group as that of the substituent in the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2, preferably a N,N-di-C1-4 alkylamino group, etc.), amidino group, an acyl group (e.g., the same acyl group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2, etc.), carbamoyl group, a N-mono-substituted carbamoyl group (e.g., a N-mono-C1-4 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.; phenylcarbamoyl; etc.), a N,N-disubstituted carbamoyl group (a N,N-di-C1-4 alkylcarbamoyl group such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc.; piperidinocarbamoyl; morpholinocarbamoyl; etc.), sulfamoyl group, a N-mono-substituted sulfamoyl group (e.g., a N-mono-C1-4 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, etc.; phenylsulfamoyl; p-toluenesulfamoyl; etc.), a N,N-disubstituted sulfamoyl group (e.g., a N,N-disubstituted C1-4 alkylsulfamoyl group such as N,N-dimethylsulfamoyl, etc.; a N-C1-4 alkyl-N-phenylsulfamoyl group such as N-methyl-N-phenylsulfamoyl, etc.; piperidinosulfamoyl; morpholinosulfamoyl; etc.), carboxyl group, a C1-10 alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxyl group, a C1-10 alkoxy group, a C2-10 alkenyloxy group, a C3-7 cycloalkyloxy group, an aralkyloxy group (e.g., C6-14 aryl-C1-6 alkyloxy, etc.), an aryloxy group (e.g., C6-14 aryloxy, etc.), mercapto group, a C1-10 alkylthio group, an aralkylthio group (e.g., C6-14 aryl-C1-6 alkylthio, etc.), an arylthio group (e.g., C6-14 arythio, etc.), sulfo group, cyano group, azido group, nitro group, nitroso group, a halogen atom, or the like. As for an alkyl group in said aryl-alkyl group, a C1-6 alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.) is preferred. Preferred examples of said aralkyl group, i.e., an aryl-alkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl)methyl, (2-naphthyl)methyl, and the like. Among them, benzyl, phenethyl, and the like are preferred.
As the acyl group in said acyloxycarbonyl group, for example, there are formyl, a C2-4 alkanoyl group, a C3-4 alkenoyl group, a C3-4 alkynoyl group, and the like.
As the aryl group in said aryloxycarbonyl group, for example, there are phenyl, naphthyl, and the like.
Examples of the amidated carboxyl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 include the carboxyl group amidated with an optionally substituted amino group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, and the heterocyclic group represented by the above mentioned R1 or R2, each of which may be substituted.
In the above-mentioned formula (I), examples of the heterocyclic group of the optionally substituted heterocyclic group represented by R include the same heterocyclic group as that defined with respect to the above-mentioned R1 or R2. The optionally substituted heterocyclic group represented by R may be attached to the adjacent X through any possible atom (e.g., nitrogen, carbon) in the heterocyclic group. It is preferred that the optionally substituted heterocyclic group represented by R is attached to X through nitrogen atom.
Examples of the heterocyclic group of the optionally substituted heterocyclic group represented by R (preferably, a nitrogen-containing heterocyclic group) include (i) a 5- to 7-membered heterocyclic group containing one sulfur atom, one nitrogen atom, or one oxygen atom, (ii) a 5- to 7-membered heterocyclic group containing 2 to 4 nitrogen atoms, or (iii) a 5- to 7-membered heterocyclic group containing 1 to 2 nitrogen atoms and one sulfur atom or one oxygen atom, or (iv) these heterocyclic groups may be condensed with a 5- to 6-membered ring containing 2 or less nitrogen atoms, benzene ring, or a 5-membered ring containing one sulfur atom. Each of the heterocyclic groups exemplified in (i) to (iv) may be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be either aromatic or non-aromatic.
These heterocyclic groups may have 1 to 3 substituents at any possible positions. Examples of such a substituent include the same substituent as that defined with respect to the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 or R2 (preferably, oxo group), or the like.
Specific examples of the optionally substituted heterocyclic group represented by R, in the case where the constituent carbon atom in the heterocyclic group is attached to the adjacent X, include 2-imidazolyl, 1,2,4-triazol-3-yl, 2-thiazolyl, 2-oxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzoimidazolyl, and the like.
Examples of the optionally substituted heterocyclic group represented by R, in the case where the constituent nitrogen atom in the heterocyclic group is attached to the adjacent X, include 1-pyrrolyl, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperidyl (piperidino), 1-piperazinyl, 4-morpholinyl (morpholino), 4-thiomorpholinyl, homopiperazin-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,3-thiadiazol-3-yl, 1,3-oxadiazol-3-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, tetrazol-1-yl, oxazol-3-yl, thiazol-3-yl, and partly or whole saturated, nitrogen-containing, heterocyclic groups thereof. These heterocyclic groups may have the 1 to 3 same substituent as the optional substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 and R2, and may be condensed with the above-mentioned non-aromatic, monocyclic heterocyclic group or aromatic ring such as benzene ring or the like. Specific examples, in the case where the heterocyclic group is condensed with an aromatic ring, include benzimidazol-1-yl, indol-1-yl, 1H-indazol-1-yl, and the like; preferably, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, imidazol-1-yl, morpholino (4-morpholinyl), piperidino (1-piperidyl), oxazolidin-3-yl, thiazolidin-3-yl, hydantoin-1-yl, pyrrolidino (1-pyrrolidin-1-yl), and the like, each of which may be substituted and may be condensed with benzene ring; more preferably, a nitrogen-containing, 5- to 7-membered ring that may have 1 to 2 oxo groups (e.g., 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl, 2,5-dioxohydantoin-1-yl, 2,5-dioxopyrrolidin-1-yl, etc.), with 2,5-dioxopyrrolidin-1-yl being particularly preferred.
R is preferably 
wherein ring C1 represents a 5- to 7- membered heterocyclic group which may contain 1 to 3 hetero atoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen atom, and may be substituted with the 1 to 3 same substituents of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group represented by R1 and R2.
More preferably, R is 
wherein ring C represents a 5- to 7-membered heterocyclic group which may contain one or more (1 to 3, preferably 1) hetero atoms selected from nitrogen, sulfur and oxygen, in addition to the nitrogen atom.
In the above formula (I), Y is oxygen atom, an optionally oxidized sulfur atom, or 
(wherein Ra and Rb, which may be the same or different, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring; and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group).
Examples of the optionally substituted hydrocarbon group represented by Ra, Rb, or Rc include the same group as the optionally substituted hydrocarbon group represented by the above-mentioned R1 or R2. Among them, methyl, ethyl, isopropyl, propyl, butyl, benzyl, phenethyl, 2-, 3-, or 4-pyridylmethyl, or the like is preferred as the optionally substituted hydrocarbon group represented by Ra, Rb, or Rc.
Examples of the optionally substituted acyl group represented by Ra, Rb, or Rc include the same group as the optionally substituted acyl group represented by the above-mentioned R1 or R2. In particular, benzoyl, acetyl or the like is preferred.
Examples of the optionally substituted carbamoyl group represented by Ra, Rb, or Rc include the same group as the optionally substituted carbamoyl group defined with respect to the substituent of the hydrocarbon group, acyl group, sulfonyl group, or heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted thiocarbamoyl group represented by Ra, Rb, or Rc include the same group as the optionally substituted thiocarbamoyl group defined with respect to the substituent of the optionally substituted hydrocarbon group, acyl group, sulfonyl group, or heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted sulfonyl group represented by Ra, Rb, or Rc include the same group as the optionally substituted sulfonyl group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted sulfinyl group represented by Ra, Rb, or Rc include the same group as the optionally substituted sulfinyl group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted hydroxyl group represented by Ra, Rb, or Rc include the same group as the optionally substituted hydroxyl group defined with respect to the substituent of the hydrocarbon group, acyl group, sulfonyl group, the sulfinyl group or heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted thiol group represented by Ra, Rb, or Rc include the same group as the optionally substituted thiol group defined with respect to the substituent of the hydrocarbon group, acyl group, sulfonyl group, the sulfinyl group or heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted, esterified carboxyl group represented by Ra, Rb, or Rc include the same group as the optionally substituted, esterified carboxyl group defined with respect to the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group or the heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted heterocyclic group represented by Ra, Rb, or Rc include the same group as the optionally substituted heterocyclic group defined with respect to the above-mentioned R1 or R2.
Also, examples of the 5- to 7-membered ring, in the case where Ra and Rb are combined each other to form the 5- to 7-membered ring, include a C3-7 saturated hydrocarbon ring (e.g., cyclopentane, cyclohexane, and cycloheptane) or a 5- to 7-membered, saturated heterocyclic group containing one to four heteroatoms selected from nitrogen, sulfur, and oxygen [e.g., nitrogen-containing, C3-7 saturated hydrocarbon ring (e.g., tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine), oxygen-containing, C5-7 saturated hydrocarbon (e.g., dioxolan, dioxane, dioxepane ring), etc.], preferably a C5-7 saturated hydrocarbon ring (e.g., cyclopentane, cyclohexane, cycloheptane) or an oxygen-containing, C5-7 saturated hydrocarbon ring (e.g., dioxolan, dioxane, dioxepane ring), or the like.
Preferred examples of Rc include hydrogen atom, hydroxyl group, methoxy group, ethoxy group, and the like.
Preferred examples of Y include an optionally substituted sulfur atom, or 
In the above-mentioned formula (I), when ring B represents to form a Y-containing optionally substituted 5- to 8-membered (preferably 6-membered) ring whose ring constituent atoms contain no nitrogen atom together with the carbon-double bond portion in the adjacent thiophene ring. Also, ring B may form a Y-containing lactone ring in the case where Y is 
As the 5- to 8-membered ring in the Y-containing optionally substituted 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom, for example, there is: 
wherein Ra, Rb, and Rc are as defined above; n is an integer of 0 to 4; and k is an integer of 0 to 4 (where the sum of n and k is 1 to 4); preferably, n and k represent 1, or the like as well as a ring a part or the whole of which is converted to an unsaturated bond, or the like, i.e., a ring represented by 
each of Yxe2x80x2 and Yxe2x80x3 represents carbon, sulfur or oxygen (preferably, carbon) atom; and Y and n are as defined above.
More preferred examples include: 
Further, in the above formula, the compound wherein at least one of Yxe2x80x2 or Yxe2x80x3 represents nitrogen atom, for example, 
wherein each symbol is as defined above, or a salt thereof can be produced by the process as described hereinafter and has the activities as described hereinafter.
The Y-containing optionally substituted 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom may further have 1 to 4 substituents other than the substituent shown with respect to the Y portion, for example, the 1 to 4 same substituents as those defined with respect to the substituent of the heterocyclic group of R1 or R2; preferably, those selected from an aliphatic-chain hydrocarbon group [e.g., an alkyl group (preferably, a C1-10 alkyl group), an alkenyl group (preferably, a C2-10 alkenyl group), an alkynyl group (preferably, a C2-10 alkynyl group), an optionally substituted acyl group, a halogen atom, etc.; more preferably, a C1-10 alkyl group (particularly, a C1-6 alkyl group) and a halogen atom (e.g., chlorine, bromine, iodine, or fluorine).
In the above-mentioned formula (I), ring A may have, at any possible position on its ring, 1 to 4, preferably one or two, more preferably one, substituents that may be the same or different. As for said substituent on ring A, there is employed, for example, a halogen atom, nitro group, an optionally substituted alkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group, or an optionally substituted aromatic ring group.
Examples of the halogen atom as the substituent on ring A include fluorine, chlorine, bromine, and iodine.
Examples of the alkyl group of the optionally substituted alkyl group as the substituent on ring A include any of a C1-10 straight chain alkyl group, a C3-10 branched chain alkyl, and a C3-10 cyclic alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
Examples of the substituent in the optionally substituted alkyl group as the substituent on ring A include the same substituent as that defined with respect to the hydrocarbon group, acyl group, sulfonyl group, the sulfiniyl group or heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted hydroxyl group as the substituent on ring A include an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted heterocyclic group or an optionally esterified carboxy group.
Examples of the substituents of the optionally substituted hydrocarbon group, the optionally substituted acyl group, the optionally substituted sulfonyl group, the optionally substituted sulfinyl group and the optionally substituted heterocyclic group include the same substituents as those of the optionally substituted hydrocarbon group, the optionally substituted acyl group, the optionally substituted sulfonyl group, the optionally substituted sulfinyl group or the optionally substituted is heterocyclic group represented by the above-mentioned R1 or R2. Further, examples of the optionally substituted carbamoyl group and the optionally esterified carboxy group include the same groups as those defined with respect to the substituents of the optionally substituted hydrocarbon group, the optionally substituted acyl group, the optionally substituted sulfonyl group, the optionally substituted sulfinyl group or the optionally substituted heterocyclic group represented by the above-mentioned R1 or R2.
As the optionally substituted hydroxyl group as the substituent of ring A, preferably, there is a C1-6 alkoxy group or hydroxyl group, more preferably a C1-6 alkoxy group, most preferably a C1-3 alkoxy group, and particularly, methoxy group.
Examples of the optionally substituted thiol group as the substituent of ring A include the same optionally substituted thiol group as that defined with respect to the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group or the heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted amino group as the substituent of ring A include the same optionally substituted amino group as that defined with respect to the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group or the heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted acyl group as the substituent of ring A include the same optionally substituted acyl group as that represented by the above-mentioned R1 or R2.
Examples of the optionally esterified carboxyl group as the substituent of ring A include the same optionally esterified carboxyl group as that defined with respect to the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group or the heterocyclic group represented by the above-mentioned R1 or R2.
Examples of the optionally substituted aromatic ring as the substituent on ring A include a C6-4 aromatic hydrocarbon group such as phenyl, naphthyl, anthryl, or the like as well as a 5- to 7-membered hetero-aromatic residue having heteroatoms(s) selected from nitrogen, sulfur, and oxygen, such as pyridyl, furyl, thienyl, imidazolyl, thiazolyl, or the like.
The substituent(s) on ring A are located preferably at the 3-position and/or 4-position on ring A. In the case where these substituents on ring A are adjacent each other, the adjacent substituents may be combined to form a ring represented by xe2x80x94(CH2)mxe2x80x94 or xe2x80x94Oxe2x80x94(CH2)1xe2x80x94Oxe2x80x94 [wherein, m represents an integer of 3 to 5 and 1 represents an integer of 1 to 3]. Such a ring includes a 5- to 7-membered ring that is formed with the carbon atoms in the benzene ring.
It is preferred that ring A is substituted with at least one optionally substituted hydroxyl group, preferably a C1-6 alkoxy group or hydroxyl group, more preferably a C1-6 alkoxy group, most preferably a C1-3 alkoxy group, in particular, methoxy group. More preferably, ring A is substituted with one optionally substituted hydroxyl. Specifically, for example, it is preferred that the 4-position in ring A is substituted with an optionally substituted hydroxyl group (particularly, methoxy group).
Preferred examples of the compound represented by the above-mentioned formula (I) include a compound, wherein alk is methylene, G is a halogen atom such as chlorine atom, etc., X is xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5), R is an optionally substituted amino group; ring B is an optionally substituted 5- to 8-membered ring containing Y, Y is an optionally substituted sulfur atom or 
and ring A is substituted with a C1-6 alkoxy group or hydroxyl group, a prodrug thereof or a salt thereof; more preferably a compound, wherein alk is methylene, G is a halogen atom such as chlorine atom, etc., X is xe2x80x94(CH2)qxe2x80x94 (q represents 0, i.e., a bond), R is 
(wherein C is as defined above), ring B is a ring represented by 
[wherein Yxe2x80x2 and Yxe2x80x3 represent carbon, sulfur, oxygen atom (preferably carbon), respectively and Y and n are as defined above (preferably an optionally oxidized sulfur atom or 
n is as defined above (preferably 1)] which may be substituted with 1 to 4 substituents selected from a C1-6 alkyl group and a halogen atom, and ring A is substituted with a C1-6 alkoxy group or hydroxyl group (preferably substituted with a C1-6 alkoxy group at the 4-position in ring A), a prodrug thereof or a salt thereof.
Preferably examples of such a compound include;
3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione, an optically active substance thereof or a salt thereof;
3-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1,3-oxazolidine-2,4-dione, an optically active substance thereof or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione, an optically active substance thereof or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-(2,5-pyrrolidinedione or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
3-{[3-chloro-4-(4-methoxyphenyl)-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-1,3-thiazolidine-2,4-dione or a salt thereof;
1-{[3-chloro-4-(4-methoxyphenyl)-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
2-aminomethyl-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4 xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridine, an optically active substance thereof or a salt thereof;
1-{[3-chloro-4-(4-hydroxyphenyl)-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione or a salt thereof;
4-{3-chloro-2-(2,5-dioxo-1-pyrrolidinyl)methyl}-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-4-yl}phenyl diisobutyl phosphate or a salt thereof; or
butyl 4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methul]-7,7-dioxido-5,8-dihydro-6H-thiopyrano[4xe2x80x2,3xe2x80x2:4,5]thieno[2,3-b]pyridin-4-yl}phenyl carbonate or a salt thereof.
In addition, preferred examples of the compound represented by the above-mentioned formula (I) include a compound, wherein G is chloridne atom, X is xe2x80x94(CH2)qxe2x80x94 (q represents an integer of 0 to 5. ), R is an optionally substituted amino group, ring B is a Y containing optionally substituted 5- to 8-membered ring, Y is 
(wherein, Ra and Rb, which may be the same or different, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring), and ring A is substituted with a C1-6 alkoxy group. Example of such a compound include:
3-chloro-2-[(2,5-dioxopyrrolidin-1-yl)methyl]-5,6,7,8-tetrahydro-7-oxo-4-(4-methoxyphenyl)[1]-benzothieno[2,3-b]pyridine ethylene ketal or a salt thereof, or the like.
As for a salt of the compound represented by the formula (I) in the present invention [hereinafter referred to as compound (I)] and a salt of the starting compound for the production of compound (I), a pharmaceutically acceptable salt is preferred. Examples thereof include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Preferred examples of the salt with an inorganic base include alkali metal salts such as the sodium salt, the potassium salt, and the like; alkaline earth metal salts such as the calcium salt, the magnesium salt, and the like; as well as an aluminum salt, an ammonium salt, and the like. Preferred examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, and the like. Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferable examples of the salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid, and the like.
Compound (I) or its salt may be in the form of a prodrug thereof. The prodrug of compound (I) or its salt refers to a compound that is converted into compound (I) or its salt by a reaction with an enzyme, gastric acid, or the like under a physiological condition in the living body, namely, [1] a compound that is converted into compound (I) or its salt by an enzymatic oxidation, reduction, hydrolysis, or the like and [2] a compound that is converted into compound (I) or its salt by hydrolysis with gastric acid or the like. Examples of the prodrug of compound (I) or its salt include a compound or its salt, wherein the hydroxyl group in compound (I) or its salt is acylated, alkylated, phosphorylated, or converted into the borate (e.g., a compound or its salt, wherein the hydroxyl group in compound (I) or its salt is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or dimethylaminomethylcarbonyloxy, etc.), a compound or its salt, wherein the carboxyl group in compound (I) or its salt is esterified or amidated (e.g., a compound or its salt or the like, wherein the carboxyl group in compound (I) or its salt is subjected to ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonyl esterification, or conversion into the methyl amide), and the like. These prodrugs can be produced according to a per se known method or its modified method.
Moreover, the prodrug of compound (I) or its salt may be a compound that is converted into compound (I) or its salt under a physiological condition as described in xe2x80x9cIyakuhin no Kaihatu (Development of Drugs)xe2x80x9d, Vol. 7, Bunishi Sekkei (Molecular Design), Hirokawa Shoten, 1990, pages 163-198.
Compound (I) or its salt may be labeled with an isotope (e.g., 3H, 14C, 35S, 125I, etc.) or the like.
When compound (I) of the present invention is a racemate, it can be separated into the corresponding (S)-form and (R)-form according to a conventional optical resolution method. The present invention includes each optically active substance (compound) and a racemate.
The above-mentioned compound (I) can be produced in the following manner. That is,
Process A 
wherein alk represents an optionally substituted lower alkylene group; Q represents a leaving group; X1 represents oxygen atom or an optionally oxidized sulfur atom; and the other symbols are as defined above.
In the general formula (II-1), examples of the leaving group represented by Q include halogen, preferably chlorine, bromine, or iodine, and a hydroxyl group activated by esterification such as a residue of organic sulfonic acid (e.g., p-toluenesulfonyloxy group, methansulfonyloxy group, etc.), a residue of organic phosphoric acid such as diphenylphosphoryloxy group, dibenzylphosphoryloxy group, dimethylphosphoryloxy group, and the like.
In this process, (II-1) is reacted with (III) in the presence of a base to produce (I-1). The reaction of (II-1) with (III) is carried out in an appropriate solvent. Examples of said solvent include aromatic hydrocarbon such as benzene, toluene, xylene, etc.; ether such as dioxane, tetrahydrofuran (THF), dimethoxyethane, or the like; alcohol such as methanol, ethanol, propanol, etc.; ethyl acetate; acetonitrile; pyridine; N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); chloroform; dichloromethane; 1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; acetone; 2-butanone; and a mixture thereof. The reaction of (II-1) with (III) is carried out in the presence of an appropriate base such as an alkali metal salt, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc.; silver carbonate (Ag2CO3); sodium hydride; potassium hydride; an amine, for example, pyridine, triethylamine, N,N-dimethylaniline, 1,5-diazabicyclo[4.3.0]non-5ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; or the like. The amount of the base to be used is preferably about 1-5 molar equivalents for compound (II-1). This reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably xe2x88x9210xc2x0 C. to 100xc2x0 C.
The thus-obtained thienopyridine derivative (I-1) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
Process B 
wherein each symbol is as defined above.
In this process, (II-2) is reacted with (IV) in the presence of a base to produce (I-2). The reaction of (II-2) with (IV) is carried out in an appropriate solvent. Examples of said solvent include aromatic hydrocarbon such as benzene, toluene, xylene, etc.; ether such as dioxane, tetrahydrofuran, dimethoxyethane, etc.; alcohol such as methanol, ethanol, propanol, etc.; ethyl acetate; acetonitrile; pyridine; N,N-dimethylformamide (DMF); dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); 1-methyl-2-pyrrolidone; 1,3-dimethyl-2-imidazolidinone; chloroform; dichloromethane; 1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; acetone; 2-butanone; and a mixture thereof. The reaction of (II-2) with (IV) is carried out in the presence of an appropriate base such as an alkali metal salt, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc.; a metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; an amine for example, pyridine, triethylamine, N,N-dimethylaniline, etc., sodium hydride; potassium hydride; or the like. The amount of the base to be used is preferably about 1-5 molar equivalents for compound (II-2). This reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably xe2x88x9210xc2x0 C. to 100xc2x0 C. The present reaction, also, is carried out by using an excess amount of (IV) as the base.
The thus-obtained thienopyridine derivative (I-2) can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
Process C 
[wherein ring B1 represents the formation of a Y1-containing optionally substituted 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y1 represents sulfur atom or 
and the other symbols are as defined above.
In this process, (I-3) is subjected to oxidation to produce (I-4). This reaction is carried out in an appropriate solvent in the presence of an oxidizing agent or, if necessary, a catalyst. Examples of said solvent include a high polar aprotic solvent such as 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, etc.; aromatic hydrocarbon such as benzene, toluene, xylene, etc.; ether such as dioxane, tetrahydrofuran, dimethoxyethane, etc.; ethyl acetate; chloroform; dichloromethane; 1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; and a mixture thereof. As the oxidizing agent, for example, there is hydrogen peroxide solution, peracetic acid, metachloroperbenzoic acid, cumene hydroperoxide, tert-butyl hydroperoxide, activated DMSO, manganese dioxide, nitric acid, or the like. As the catalyst, preferably, a complex containing a metal is used. Examples of the metal include vanadium, titanium, ruthenium, rhenium, tungsten, manganese, cobalt, etc. Among them, vanadium is preferred. Examples of the vanadium complex include vanadium oxides such as vanadium oxide acetylacetonate, vanadium oxide benzoylacetonate, vanadium oxide picolinate, vandium (V) oxide, vanadium (IV) oxide acetate, vanadium (IV) oxide sulfate hydrate, etc.; vanadium nitrides such as vanadium nitride; vanadium chlorides such as vanadium oxytrichloride, vanadium dichloride, vanadium tetrachloride, etc.; vanadium oxide trimethoxide; vanadium oxide triethoxide; vanadium oxide tri-n-propoxide; vanadium oxide triisopropoxide, vanadium tri-n-butoxide; vanadium oxide tri-sec-butoxide; vanadium oxide-t-butoxide; vanadium oxide xcex2-hydroxyquinolyl; vanadium oxide xcex2-hydroxypyridyl; and the like. The amount of the oxidizing agent is preferably an equivalent or an excess amount (for example, about 1-50 molar equivalents) for compound (I-3). Further, the amount of the catalyst to be used is 0.0000001 to 10 equivalents, preferably 0.0000005 to 1 equivalent for compound (I-3). This reaction is carried out usually at xe2x88x9270xc2x0 C. to 150xc2x0 C., preferably -60xc2x0 C. to 120xc2x0 C. and the reaction time is usually 1-100 hours.
The thus-obtained thienopyridine derivative (I-4) can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
Process D 
wherein Z1 represents an optionally substituted heterocyclic group; qxe2x80x2 represents an integer of 0 to 4; Gxe2x80x2 represents a halogen atom; and the other symbols are as defined above.
In this process, the compound represented by the general formula (II-3) is first reacted with a corresponding amount of triphenylphosphine to produce a phosphonium salt derivative represented by the general formula (VI). This reaction is carried out in a solvent and examples of said solvent include aromatic hydrocarbon such as benzene, toluene, xylene, etc.; ether such as tetrahydrofuran, dioxane, dimethoxyethane, etc.; acetonitrile; and a mixture thereof. This reaction is carried out at 10xc2x0 C. to 200xc2x0 C., preferably 30xc2x0 C. to 150xc2x0 C. for 0.5-50 hours.
Then, the phosphonium salt derivative (VI) and an aldehyde derivative (VII) are subjected to condensation reaction to produce (VIII). The condensation reaction of (VI) and (VII) is carried out in an appropriate solvent in the presence of a base. Examples of said solvent include alcohol such as methanol, ethanol, propanol, etc.; ether such as ethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, etc.; aromatic hydrocarbon such as benzene, toluene, xylene, etc.; dichloromethane; 1,2-dichloroethane; N,N-dimethylformamide; dimethyl sulfoxide; and a mixture thereof. Examples of the base include an alkali metal hydride such as sodium hydride, potassium hydride, etc.; an alkoxide such as sodium ethoxide, sodium methoxide, potassium ethoxide, potassium tert.-butoxide, etc.; an organic lithium compound such as methyllithium, butyllithium, phenyllithium, etc.; sodium amide; and the like. The amount of the base to be used is preferably about 1-1.5 molar equivalents for compound (VI). This reaction is carried out usually at xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably xe2x88x9220xc2x0 C. to 50xc2x0 C. The reaction time is 0.5-20 hours.
Although (VIII) is obtained as an isomeric mixture of the (E) form and the (Z) form with respect to the newly formed double bond, these (E) and (Z) forms, after separation into each isomer or as a mixture thereof without separation, are subjected to reduction to produce (I-5). This reduction is carried out by a conventional method in a solvent under an atmosphere of hydrogen in the presence of a catalyst such as a palladium catalyst (palladium-carbon, palladium black, etc.), a platinum catalyst (platinum dioxide, etc.), Raney nickel, or the like. Examples of said solvent include alcohol such as methanol, ethanol, propanol, etc.; ether such as ethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, etc.; aromatic hydrocarbon such as benzene, toluene, xylene, etc.; dichloromethane; 1,2-dichloroethane; ethyl acetate; acetonitrile; acetone; 2-butanone; N,N-dimethylformamide; dimethyl sulfoxide; and a mixture thereof. The pressure of hydrogen atmosphere is 1-150 atmospheric pressure, preferably 1-20 atmospheric pressure. The thus-obtained thienopyridine derivative (I-5) can be isolated and purified according to a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
Process E 
wherein each symbol is as defined above.
In this process, (II-1) is reacted with an alkali metal salt of diformylimide such as the sodium salt of diformylimide to be converted into a formylamino compound (I-6), which is then reacted with an acid to produce (I-7).
The reaction of compound (II-1) with an alkali metal salt of diformylimide such as the sodium salt of diformylimide is carried out in the same manner as that in Process A.
Compound (I-7) is produced by subjecting the formylamino compound (I-6) to hydrolysis in the presence of an acid. The hydrolysis of compound (I-6) is carried out in a water-containing solvent. Examples of said solvent include ether such as dioxane, tetrahydrofuran, dimethoxyethane, etc.; alcohol such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, etc.; acetonitrile; N,N-dimethylformamide; dimethyl sulfoxide; acetone; 2-butanone; acetic acid; and a mixture thereof. The acid is, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, or the like. The amount of the acid to be used is preferably a large excess amount, e.g., about 5-50 molar equivalents for compound (I-6). This reaction is carried out usually at 30xc2x0 C. to 150xc2x0 C., preferably about 50xc2x0 C. to 120xc2x0 C. and the reaction time is usually 1-100 hours. Furthermore, the sulfonylamino derivative of compound (I-7) is produced according to Process F described in JP 10-36374 A, and the acylamino derivative thereof is produced according to its Process I.
The thus-obtained thienopyridine derivative can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
Compound (I-7) obtained by Process E is also produced by the Gabriel method, wherein compound A, obtained by the reaction of compound (II-1) with an alkali metal salt of phthalimide such as the potassium salt of phthalimide, is decomposed by the reaction thereof with an acid or hydrazine (Process F).
Process F 
wherein each symbol is as defined above.
The reaction of compound (II-1) with an alkali metal salt of phthalimide such as the potassium salt of phthalimide is carried out in the same manner as that of Process A. Compound (I-7) is produced by subjecting to decomposition reaction in the presence of an acid or hydrazine. The decomposition reaction of compound (I-8) is carried out in the presence of water. As for said solvent, there can be used the same solvent as that used in the hydrolysis of compound (I-6) in Process E. As for said acid, there can be used hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, or the like.
The thus-obtained thienopyridine derivative (I-7) and (I-8) can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
Process G 
wherein each symbol is as defined above.
In this method, (II-1) is reacted with (XII) in the presence of a base to produce (I-9). The reaction of (II-1) with (XII) is carried out in an appropriate solvent. Examples of said solvent include aromatic hydrocarbon such as benzene, toluene, xylene, and the like; ether such as dioxane, tetrahydrofuran, dimethoxyethane, and the like; alcohol such as methanol, ethanol, propanol, and the like; ethyl acetate; acetonitrile; pyridine; N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); chloroform; dichloromethane; 1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; acetone; 2-butanone; and a mixture thereof. The reaction of (II-1) with (XII) is carried out in the presence of an appropriate base such as an alkali metal salt, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, or the like; an amine such as pyridine, triethylamine, N,N-dimethylaniline, or the like; sodium hydride; potassium hydride; n-butyllithium; t-butyllithium; lithium diisopropylamide (LDA); or the like. The amount of the base to be used is preferably about 1-5 molar equivalents for compound (II-1). This reaction is carried out usually at xe2x88x9270xc2x0 C. to 150xc2x0 C., preferably xe2x88x9270xc2x0 C. to 100xc2x0 C. This reaction is also carried out by the use of an excess amount of (XII) as the base.
The thus-obtained thienopyridine derivative (I-9) can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
Further, the compound represented by the general formula (II-1), which is the starting material in the above-mentioned Process A, Process E, Process F, and Process G, can be produced, for example, in the following manner. 
wherein each symbol is as defined above.
According to a process described in Journal of Medicinal Chemistry, 17, 624 (1974), compound (XI) is produced by reaction of compound (IX), sulfur, and compound (X) in the presence of a base in a solvent. Examples of said solvent include aromatic hydrocarbon such as benzene, toluene, xylene, and the like; ether such as dioxane, tetrahydrofuran, dimethoxyethane, and the like; alcohol such as methanol, ethanol, propanol, and the like; chloroform; dichloromethane; 1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; N,N-dimethylformamide (DMF); dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); 1-methyl-2-pyrrolidone; 1,3-dimethyl-2-imidazolidinone; and a mixture thereof. The reaction is carried out in the presence of an appropriate base such as an alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.; a metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; an amine such as triethylamine, diethylamine, morpholino, piperidine, N,N-dimethylaniline, or the like. The amount of this base is preferably about 1-5 molar equivalents for compound (IX). This reaction is carried out usually at xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably xe2x88x9210xc2x0 C. to 100xc2x0 C. Then, compound (II-1) is produced by the reaction of compound (XI) and compound (XII). The reaction of (XI) and (XII) is carried out in a solvent in the presence of an appropriate acid such as a Lewis acid, for example, aluminum chloride, zinc chloride, or the like; hydrochloric acid; sulfuric acid; trifluoroacetic acid; p-toluenesulfonic acid; or the like. Examples of said solvent include aromatic hydrocarbon such as benzene, toluene, xylene, and the like; ether such as dioxane, tetrahydrofuran, dimethoxyethane, and the like; alcohol such as methanol, ethanol, propanol, and the like; ethyl acetate; N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); chloroform; dichloromethane; 1,2-dichloroethane; 1,1,2,2,-tetrachloroethane; and a mixture thereof. The amount of compound (VIII) to be used is preferably about 1.0-2.0 molar equivalents for compound (VII). The amount of the acid is preferably about 0.05-2.0 molar equivalents for compound (VII). This reaction is carried out usually at 0xc2x0 C. to 200xc2x0 C., preferably about 20xc2x0 C. to 120xc2x0 C. The reaction time is 0.5-20 hours, preferably 1-10 hours.
The thus-obtained compound represented by the general formula (II-1) can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography, and the like.
In the case where the thienopyridine derivatives produced by Process A to Process G have isopropoxy group as a substituent on ring A, the isopropoxy group can be converted into hydroxyl group by treatment with titanium tetrachloride. This reaction is carried out in a solvent such as chloroform, dichloromethane, carbon tetrachloride, or the like at xe2x88x9250xc2x0 C. to 30xc2x0 C., preferably about xe2x88x9210xc2x0 C. to 20xc2x0 C.
Since compound (I) or a salt thereof of the present invention has anti-inflammatory activity and further anti-arthritic activity, it can be used in the prevention or treatment of all arthritic diseases with inflammatory conditions in joints. The arthritic diseases include, for example, chronic rheumatoid arthritis and the like.
Also, compound (I) of the present invention or a salt thereof can be used in the prevention and treatment of rheumatism and the like.
Further, compound (I) of the present invention or a salt thereof has excellent suppressing effect on bone resorption and is useful in the prevention and treatment of bone destruction, osteoporosis, and the like, which accompany arthritis. Furthermore, the compound of the present invention has suppressing effect on immune cytokine production and is also useful in the prevention and treatment of diseases associated with immune reactions, and/or in the prevention and treatment of rejection reaction after organ transplantation.
Furthermore, compound (I) of the present invention or a salt thereof has suppressing effect on the production of immune cytokines [e.g., interleukin-2 (IL-2), interferon-xcex3 (IFN-xcex3), etc.] and is useful in the prevention and treatment of diseases associated with immune including autoimmune diseases.
Examples of these diseases include systemic lupus erythematosus, inflammatory bowel disease (ulcerative colitis, Crohn""s disease), multiple sclerosis, psoriasis, chronic hepatitis, urinary bladder carcinoma, breast carcinoma, uterine cervix carcinoma, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, colon cancer, rectal cancer, infection with Helicobacter pylori, Hodgkin""s disease, insulin-dependent diabetes mellitus, malignant melanoma, multiple myeloma, non Hodgkin""s lymphoma, non-small cell lung carcinoma, ovarian cancer, peptic ulcer, prostatic carcinoma, septic shock, tuberculosis, sterility, arteriosclerosis, Behcet""s disease, asthma, atopic dermatitis, nephritis, systemic mycosis, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia, chronic pancreatitis, herpes simplex virus infection, varicella-zoster virus infection, AIDS, human papilloma virus infection, influenza, invasive staphylococcal infection, peripheral vascular diseases, sepsis, interstitial hepatic diseases, regional ileitis, and the like. Compound (I) of the present invention or a salt thereof is used, among others, in prevention or treatment of lupus erythematosus, chronic hepatitis, interstitial hepatic diseases, asthma, psoriasis, ulcerative colitis, Crohn""s disease, regional ileitis, multiple sclerosis, or the like.
Also, compound (I) of the present invention or a salt thereof is useful in the prevention and treatment of rejection reaction after organ transplantation.
Moreover, compound (1) of the present invention or a salt thereof is useful as a T-cell differentiation modifying drug. A T-cell differentiation modifying drug is a generic name of a compound which modifies differentiation of T lymphocyte into Type-1 T lymphocyte (T1 cell) or Type-II T lymphocyte (T2 cell). T1 cells are T lymphocytes mainly producing IFN-xcex3, IL-2 and TNFxcex2 as cytokines, and include CD4+ T lymphocytes and CD8+ T lymphocytes. T2 cells are T lymphocytes mainly producing IL-4, IL-5 and IL-10 as cytokines and include CD4+ T lymphocytes and CD8+ T lymphocytes. Therefore, a T-cell differentiation modifying drug can be used for preventing or treating arthritis and the above-mentioned other diseases.
The toxicity of the compound of the present invention is low.
Therefore, compound (I) of the present invention or a salt thereof may be used as prophylactic and therapeutic drugs of inflammatory diseases, arthritis, rheumatism, rheumatoid arthritis, or autoimmune diseases; as prophylactic and therapeutic drugs of rejection reaction after organ transplantation; and as prophylactic and therapeutic drugs of bone destruction, osteoporosis, and the like, which accompany arthritis, in mammalian animals including human being (e.g., human being, horse, cow, pig, dog, cat, rat, mouse, etc.).
The dosage of compound (I) and a salt thereof can be selected in various ways depending on the administration route and the symptom of the patient to be treated. Usually, as compound (I) per an adult, the daily dosage can be selected from a range of about 1 mg to about 500 mg, preferably about 5 mg to about 100 mg in the case of oral administration, and from a range of about 0.1 mg to about 100 mg, further preferably about 0.3 mg to about 10 mg in the case of parenteral administration. The dosage can be administered by dividing 1-3 times per day.
The compound (I) or a salt thereof of the present invention can be compounded with a pharmaceutically permissible carrier and can be orally or parenterally administered as solid formulations such as tablets, capsules, granules, powders, or the like; or liquid formulations such as syrups, injections, or the like. Also, there can be prepared formulations for transdermal administration such as patchings, cataplasms, ointments (including creams), plasters, tapes, lotions, solutions, suspensions, emulsions, sprays, and the like.
As for the pharmaceutically acceptable carrier, a variety of organic or inorganic carrier substances, which have been conventionally employed as formulation materials, are used, and are compounded as an excipient, a lubricant, a binding agent, and a disintegrator in solid formulations; a solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, and an analgesic in liquid formulations. Also, as needed, formulation additives such as a preservative, an antioxidant, a stabilizer, a coloring agent, a sweetening agent, and the like can be used.
Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include magnesium stearate, potassium stearate, talc, colloidal silica, and the like. Preferable examples of the binding agent include crystalline cellulose, xcex1-starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like. Preferable examples of the disintegrator include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like.
As needed, for the purpose of taste masking, enteric coating, or prolonged action, oral formulations can be coated by a per se known method. Examples of this coating agent include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate phthalate, Eudragit (manufactured by Rohm Company, methacrylic acid-acrylic acid copolymer), and the like.
Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisamiomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; hydrophilic high molecular weight substances such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose hydroxypropyl cellulose, etc.; and the like. Preferred examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, and the like. Preferred examples of the buffering agent include buffer solutions of a phosphate, an acetate, a carbonate, a citrate, or the like. Preferred examples of the analgesic include benzyl alcohol and the like. Preferred examples of the preservative include paraoxybenzoic acid ester, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferred examples of the antioxidant include sulfite, ascorbic acid, and the like.
Moreover, compound (I) or a salt thereof can be administered as a single formulation, or simultaneously or at temporal intervals together with [1] a cyclooxygenase inhibitor (a Cox-I, Cox-II inhibitor), [2] a disease-modifying anti-rheumatic drug and an immunodepressant, [3] a biological preparation, [4] an analgesic and an anti-inflammatory agent, [5] a therapeutic drug for bone disease, [6] p38MAP kinase inhibitor and/or TNF-xcex1 production inhibitor, [7] c-JUN N-terminal kinase (JNK) inhibitor, or the like.
[1] Examples of cyclooxygenase inhibitors (Cox-I, Cox-II inhibitors) include celecoxib, rofecoxib, salicylic acid derivatives such as aspirin, diclofenac, indomethacin, loxoprofen, and the like. The oral doses of these drugs are, for example, about 100-200 mg/day for celecoxib, about 10-30 mg/day for rofecoxib, 1000-4500 mg/day for salicylic acid derivatives such as aspirin, about 25-75 mg/day for diclofenac, about 50-150 mg/day for indomethacin, and about 60-180 mg/day for loxoprofen.
[2] Examples of disease-modifying anti-rheumatic drugs and immunodepressants include methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, oral gold compounds, and the like. The oral doses of these drugs are, for example, about 2.5-7.5 mg/week for methotrexate, about 20-100 mg/day for leflunomide, about 1-5 mg/day for Prograf, about 500-2000 mg/day for sulfasalazine, about 100-600 mg/day for D-penicillamine, and about 3-6 mg/day for oral gold compounds.
[3] Examples of biological preparations include monoclonal antibodies (e.g., anti-TNF-xcex1 antibody, anti-IL-12 antibody, anti-IL-6 antibody, anti-ICAM-I antibody, anti-CD4 antibody, etc.), soluble receptors (e.g., soluble TNF-xcex1 receptor, etc.), and protein ligands (IL-1 receptor antagonist, etc.). The oral doses of these drugs are, for example, about 0.1-50 mg/kg/day, preferably 0.5-20 mg/kg/day.
[4] Examples of analgesics and anti-inflammatory agents include centrally acting analgesics (e.g., morphine, codeine, pentazocine, etc.), steroids (e.g., prednisolone, dexamethasone, betamethazone, etc.), and anti-inflammatory enzyme agents (e.g., bromelain, lysozyme, proctase, etc.). The oral doses of these drugs are, for example, about 1-1000 mg/day, preferably about 5-300 mg/day, for centrally acting analgesics, about 0.1-400 mg/day, preferably about 5-100 mg/day, for steroids, and about 1-100 mg/day, preferably about 5-40 mg/day, for anti-inflammatory enzyme agents.
[5] Examples of therapeutic drugs for bone diseases (e.g., bone fracture, refracture, osteoporosis, osteomalacia, Paget""s disease of bone, ankylosing spondylitis, chronic rheumatoid arthritis, denerative gonarthritis, destruction of joint tissues in related diseases, etc.) include calcium preparations (e.g., calcium carbonate, etc.), calcitonin preparations, vitamin D preparations (e.g., xcex1-calcidol, etc.), sex hormones (e.g., estrogen, estradiol, etc.), prostaglandin A1, bisphosphonates, ipriflavons, fluorine compounds (e.g., sodium fluoride, etc.), vitamin K2, bone morphogenic protein (BMP), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF)-xcex2, insulin-like growth factor-1 and -2 (IGF-1, -2), parathyroid hormone (PTH), and compounds described in European Patent Publications No. EP 376197 A1, EP 460488 A1, and EP 719782 A1(e.g., (2R,4S)-(xe2x88x92)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide, etc.).
[6] Examples of p38MAP kinase inhibitor and/or TNF-xcex1 inhibitor include:
i) a compound represented by the formula: 
wherein R1 is hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted amino group or an acyl group; R2xe2x80x2 is an optionally substituted pyridyl group; and R3xe2x80x2 is an optionally substituted aromatic group, a salt thereof or a prodrug thereof;
ii) a compound represented by the formula: 
wherein R1a is hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group or an acyl group; R2a is an optionally substituted aromatic group; R3a is hydrogen atom, an optionally substituted pyridyl group or an optionally substituted aromatic hydrocarbon group; Xa is oxygen atom or an optionally oxidized sulfur atom; Ya is a bond, oxygen atom, an optionally oxidized sulfur or NR4a (wherein R4a is hydrogen atom, an optionally substituted hydrocarbon group or an acyl); and Za is a bond or an optionally substituted divalent straight chain hydrocarbon group, a salt thereof or a prodrug thereof; for example,
N-[5-(2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide;
N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide;
N-[4-[4-(4-methoxypheny)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide;
N-[4-[2-(4-fluoropheny)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;
N-[4-[2-ethyl-4-(3-methylpheny)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;
N-[4-[4-(3-methylpheny)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;
N-[4-[2-butyl-4-(3-methylpheny)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;
N-[4-[4-(3-methylpheny)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide;
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylbutylamide;
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;
N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzaminde;
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionaminde;
N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;
N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine;
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;
N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;
N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine;
N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl] -N-(2-phenylethyl)amine;
N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine;
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide;
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide;
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide;
N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)-amine;
N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)-amine;
N-[4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine;
(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide;
(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide;
(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;
(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;
(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;
(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;
(S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;
(R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethyl-amino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;
N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]nicotinamide;
N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;
N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;
N-[5-(2-benzylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;
N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]nicotinamide;
N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide;
N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide;
N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methyl-phenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide;
(S)-N-(l-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(R)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine;
(R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine;
(S)-N-(1-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(R)-N-(l-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfophenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(S)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
(R)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine;
or a salt thereof;
iii) a compound represented by the formula: 
wherein a is N or C; b is CH when a is N, or O when a is C; xe2x95x90 is a bond or a double bond depending upon whether the azole ring being imidazole ring or oxazole ring; Zb is N or CH; Wb is xe2x80x94NR6bxe2x80x94Ybxe2x80x94 (R6b is H, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-3 alkyl, C6-18 aryl, C3-18 heteroalkyl, C7-19 aralkyl or C4-19 heteroaralkyl; xe2x80x94Ybxe2x80x94 is C1-4 alkylene or a bond), xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; R2b is phenyl (optionally substituted with 1 or more substitutes selected from the group consisting of a halogen atom, trifluoromethyl, cyano, amide, thioamide, carboxylate, thiocarboxylate, C1-4 alkoxy, amino, and mono- or di- C1-4 alkylamino); R3b is H, a halogen atom, C1-10 alkyl, C1-4 alkenyl, C3-10 cycloalkyl, C3-18 heterocycloalkly, C6-18 aryl, C3-18 heteroaryl, or xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94C(NH)NH2 (each of which may be substituted with 1 to 4 substituents selected from the group consisting of C1-4 alkyl optionally substituted with hydroxyl, a halogen atom, C1-4 alkyl substituted with halogen, hydroxyl, C1-4 alkoxy, C1-4 alklthio, carboxy, carbonyl optionally substituted with C1-6 alkyl or C1-6 alkoxy, amino, mono- or di- C1-4 alkylamino, and 5- to 7-membered N-containing heterocyclic group (which may contain additional one or more hetero atoms)); and R5b is C6-18 aryl, C3-18 heteroaryl or C3-12 cycloalkyl (each of which may be substituted 1 to 4 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkyl substituted with halogen, hydroxyl, C1-4 alkyl, C1-4 alkylthio, amino, mono- or di- C1-4 alkylamino and a 5- to 7-membered N-containing heterocyclic group (which may contain additional one or more hetero atoms)), a salt thereof or a prodrug thereof; and the like.
[7] As the JNK inhibitor, there are, for example, the compounds described in WO 00/35906, WO 00/35909, WO 00/35921, WO 00/64872 and WO 00/75118, and the like.